STRUCTURE/ACTIVITY RELATIONSHIPS OF C-TERMINAL NEUROPEPTIDE-Y PEPTIDE SEGMENTS AND ANALOGS COMPOSED OF SEQUENCE 1-4 LINKED TO 25-36

被引:48
作者
BECKSICKINGER, AG
JUNG, G
GAIDA, W
KOPPEN, H
SCHNORRENBERG, G
LANG, R
机构
[1] UNIV TUBINGEN,INST ORGAN CHEM,AUF DER MORGENSTELLE 18,W-7400 TUBINGEN 1,GERMANY
[2] BOEHRINGER INGELHEIM KG,PHARMAKOL ABT,W-6507 INGELHEIM,GERMANY
[3] BOEHRINGER INGELHEIM KG,PHARMACHEM ABT,W-6507 INGELHEIM,GERMANY
[4] UNIV HEIDELBERG,INST PHARMAZEUT,W-6900 HEIDELBERG,GERMANY
来源
EUROPEAN JOURNAL OF BIOCHEMISTRY | 1990年 / 194卷 / 02期
关键词
D O I
10.1111/j.1432-1033.1990.tb15638.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
C-terminal analogues of neuropeptide Y have been synthesized. The influence of chain length, single-amino-acid substitutions and segment substitutions on receptor binding, biological activity and conformational properties has been investigated. Receptor binding and in vivo assays revealed biological activity already for amino acids 28 - 36 of neuropeptide Y [neuropeptide Y-(Ac-28 - 36)-peptide] which increased with increasing chain length. Replacement of Arg25 in neuropeptide Y-(Ac-25 - 36)-peptide had no influence on binding, whereas Arg33 and Arg35 cannot be replaced by lysine or ornithine without considerable decrease in receptor binding. The introduction of conformational constraints by the 2-aminoisobutyric acid residue (Aib) in position 30 and replacing the amino acids 28 - 32 by Ala-Aib-Ala-Aib-Ala decreased receptor binding. However, the corresponding Aib-Ala-Aib-Ala-Aib-substituted analogue and a more flexible analogue with Gly5 at position 28 - 32 exhibited considerable affinity for the receptor. All these substitutions led to a decrease in postsynaptic activity. Strong agonistic activities could be detected in a series of 10 discontinuous analogues, which are constructs of N-terminal parts linked via different spacer molecules to C-terminal segments. One of the most active molecules was neuropeptide Y amino acids 1 - 4 linked to amino acids 25 - 36 through aminohexanoic acid (Ahx) [neuropeptide Y-(1 - 4-Ahx-25 - 36)-peptide].
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页码:449 / 456
页数:8
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